scholarly journals Detection of a Soluble Form of BACE-1 in Human Cerebrospinal Fluid by a Sensitive Activity Assay

2006 ◽  
Vol 52 (6) ◽  
pp. 1168-1174 ◽  
Author(s):  
Jan H Verheijen ◽  
Linda GM Huisman ◽  
Natascha van Lent ◽  
Ulf Neumann ◽  
Paolo Paganetti ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Specific Activity ◽  
Proteolytic Enzymes ◽  
Amyloid Β ◽  
Soluble Form ◽  
Amyloid Β Peptide ◽  
Activity Assay ◽  
Human Cerebrospinal Fluid ◽  
Membrane Bound ◽  
Bace 1

Abstract Background: Formation of deposits of the insoluble amyloid β-peptide is believed to be causally related with neurodegeneration in Alzheimer disease (AD). The β-peptide originates from a larger amyloid precursor protein (APP) by the action of proteolytic enzymes. The first proteolytic event leading to amyloid formation is the cleavage of APP by the membrane-bound aspartyl protease BACE-1, also known as memapsin-2. Inhibition of BACE-1 is thought to be a therapeutic approach to AD. Measuring BACE-1 activity in biological samples would be useful to elucidate the mechanism of AD and for development of AD drugs. Methods: We developed a sensitive and specific activity assay for BACE-1. The assay is based on a genetically engineered proenzyme that is specifically activated by BACE-1. The resulting active enzyme is measured with a chromogenic substrate. The use of 2 coupled reactions produces a detection limit as low as 0.4 pmol/L. Results: The assay detected BACE-1 activity in extracts of human brain tissue as well as, unexpectedly, in human cerebrospinal fluid (CSF). Gel electrophoresis and Western blotting identified the BACE-1 present in CSF as a truncated soluble form of the originally membrane-bound BACE-1. Conclusion: Detection of the soluble form of BACE-1 in CSF, a relatively easily accessible biological fluid, may be useful for monitoring the effects of drug candidates in vivo and may have diagnostic or prognostic applications.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

scholarly journals Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease

2019 ◽  
Vol 11 (507) ◽  
pp. eaav6221 ◽  
Author(s):  
Michael Ewers ◽  
Nicolai Franzmeier ◽  
Marc Suárez-Calvet ◽  
Estrella Morenas-Rodriguez ◽  
Miguel Angel Araque Caballero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Elderly Subjects ◽  
Amyloid Β Peptide ◽  
Loss Of Function ◽  
Clinical Progression ◽  
Cognitively Normal ◽  
Soluble Trem2

Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer’s disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aβ1–42 (amyloid β-peptide 1 to 42; A+) and CSF p-tau181 (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aβ1–42 and CSF p-tau181 (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau181 concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aβ1–42 and CSF p-tau181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.

scholarly journals Accumulation of Alzheimer Amyloid-β Peptide in Cultured Myocytes is Enhanced by Serum and Reduced by Cerebrospinal Fluid

1997 ◽  
Vol 56 (3) ◽  
pp. 263-272 ◽  
Author(s):  
BOZENA MAZUR-KOLECKA ◽  
JANUSZ FRACKOWIAK ◽  
RICHARD T. CARROLL ◽  
HENRYK M. WISNIEWSKI
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Amyloid Β Peptide

[P1-280]: ANALYTICAL PERFORMANCE CHARACTERISTICS OF A NOVEL IMMUNOASSAY FOR THE QUANTIFICATION OF BACE-1 IN HUMAN CEREBROSPINAL FLUID

2017 ◽  
Vol 13 (7S_Part_7) ◽  
pp. P357-P357
Author(s):  
Emeric Chassaing ◽  
Mélanie Bodnar-Wachtel ◽  
Tanja Schubert ◽  
Hugo Marcel Vanderstichele ◽  
Erik Stoops ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Performance Characteristics ◽  
Analytical Performance ◽  
Human Cerebrospinal Fluid ◽  
Bace 1

Amyloid β binding proteins in vitro and in normal human cerebrospinal fluid

1995 ◽  
Vol 191 (1-2) ◽  
pp. 79-82 ◽  
Author(s):  
Adam Golabek ◽  
Marcos A. Marques ◽  
Maciej Lalowski ◽  
Thomas Wisniewski
Keyword(s):  
Cerebrospinal Fluid ◽  
Binding Proteins ◽  
Amyloid Β ◽  
Human Cerebrospinal Fluid ◽  
Normal Human
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